Lamar was admitted to the bar in Georgia in 1847 and was a member of the Georgia House of Representatives (1853). He moved to Mississippi in 1855 and was elected to the U.S. House of Representatives the following year, serving until December 1860, when he resigned to participate in the Mississippi secession convention. He was the author of the Mississippi ordinance of secession (Jan. 9, 1861) and served in the Confederate army.

After the war Lamar taught law at the University of Mississippi (1866–73). He then served in the U.S. Congress, both in the House (1873–77) and in the Senate (1877–85), where his moderating influence during Reconstruction won him the sobriquet “the Great Pacificator.” President Grover Cleveland appointed Lamar secretary of the interior (1885) and later associate justice of the U.S. Supreme Court (1888). His most important opinion while a justice of the Court was a dissent in In re Neagle (1890), which expressed his conviction that the authority of the federal executive is limited to the powers specifically granted by the Constitution and statutes.